Hapalindole/Ambiguine Biogenesis Is Mediated by a Cope Rearrangement, C–C Bond-Forming Cascade

Abstract

Hapalindoles are bioactive indole alkaloids with fascinating polycyclic ring systems whose biosynthetic assembly mechanism has remained unknown since their initial discovery in the 1980s. In this study, we describe the fam gene cluster from the cyanobacterium Fischerella ambigua UTEX 1903 encoding hapalindole and ambiguine biosynthesis along with the characterization of two aromatic prenyltransferases, FamD1 and FamD2, and a previously undescribed cyclase, FamC1. These studies demonstrate that FamD2 and FamC1 act in concert to form the tetracyclic core ring system of the hapalindoles from cis-indole isonitrile and geranyl pyrophosphate through a presumed biosynthetic Cope rearrangement and subsequent 6-exo-trig cyclization/electrophilic aromatic substitution reaction.

A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis

“…There are very few examples of a rearrangement of a long-chain carbon moiety in natural product biosynthesis; it has only been observed as a reaction that results in a shunt product in hapalindole/ambiguine biosynthesis 29 and it is suggested in the biosynthesis of aurachin 34,43 . In merochlorin biosynthesis, both reactions are catalysed by a single enzyme, Mcl24.…”

“…Moreover, our synthetic endeavour provides additional insight into the enzymatic transformation and lends credence to this rearrangement. We demonstrate that the amalgamation of biochemical investigations into an enzymatic reaction and its cognate synthetic application harbours great potential to address complex questions and advance the fields of both biosynthetic and synthetic chemistry 28,29 .…”

Discovery of a Calcium‐Dependent Enzymatic Cascade for the Selective Assembly of Hapalindole‐Type Alkaloids: On the Biosynthetic Origin of Hapalindole U

“…[1][2][3][4][5][6][7][8][9][10][11][12] These studies,c ollectively directed towards deciphering the origin of structural complexities and diversities of hapalindole-type alkaloids,h ave thus far unraveled several layers of puzzles concerning their global biosynthetic diversifications (see Figure S1 in the Supporting Information). [1][2][3][4][5][6][7][8][9][10][11][12] These studies,c ollectively directed towards deciphering the origin of structural complexities and diversities of hapalindole-type alkaloids,h ave thus far unraveled several layers of puzzles concerning their global biosynthetic diversifications (see Figure S1 in the Supporting Information).…”

“…These include the identification of indolenine 2 derived from the enzymatic geranylation of cis-indolyl vinyl isonitrile 1 (Figure 1a), as the cryptic common biosynthetic precursor to all hapalindole-type alkaloids, [7] and establishing the enzymatic basis for halogenations in these alkaloids that account for both complexity and diversity generations. [10,11] As the enzymatic cyclizations by WelU1/ WelU3/AmbU4 proteins are induced by the geranyl group rearrangement in 2,these enzymes can be formally named as afamily of isomerocyclases. [10,11] As the enzymatic cyclizations by WelU1/ WelU3/AmbU4 proteins are induced by the geranyl group rearrangement in 2,these enzymes can be formally named as afamily of isomerocyclases.…”

Asymmetric Enzymatic Synthesis of Allylic Amines: A Sigmatropic Rearrangement Strategy

“…1 While useful in chemical synthesis, sigmatropic rearrangements are remarkably rare in biology. 2 Only a handful of enzymes that exploit such rearrangements have been identified, 3 a notable example being chorismate mutase, which catalyzes the Claisen rearrangement of chorismate to prephenate in the biosynthesis of tyrosine and phenylalanine (Scheme 1). 4 Alternatively, certain biological pathways involve sigmatropic rearrangements that are spontaneous once a given precursor has been assembled; for instance, Claisen 5 and Cope rearrangements 6 have been implicated in the prenylation of aromatic amino acid side chains.…”